Diabetic neuropathy (DN) is the most common chronic complication of diabetes, ultimately affecting half of patients with type 1 diabetes (T1DM) and leading to severe morbidity, high mortality, major physical disability, poor quality of life and estimated total annual costs of $22 billion. Due to the complex structure and anatomy of the peripheral nervous system, DN presents with a very broad spectrum of clinical symptoms and deficits, including severe pain, sensory deficits, foot ulcers and amputations. Despite the high morbidity associated with DN, most randomized clinical trials evaluating therapies for established DN have been disappointing. To date there is no pathogenetic treatment for this condition. The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive control designed to achieve near-normal glycemia is essential in reducing the risk of DN development in type 1 diabetes. However, attainable intensive glycemic control, although necessary, is insufficient to prevent adverse nervous system effects, justifying a therapeutic need to identify new drug targets to treat DN early in its course. Evidence for an important role of low-grade inflammation and of nuclear factor kappa B (NF-kB) activation in the pathogenesis of DN and in the pain syndrome associated with DN is emerging from both experimental and clinical studies. This suggests that agents with known anti-inflammatory properties, such as salicylates, may prevent the development of DN and the pain associated with DN. Salsalate (Disalcid), a pro-drug form of salicylate, is an FDA approved treatment for osteoarthritis and other rheumatologic conditions. It is a highly effective drug in blocking the IKK2/NF-:B pathway, with a large margin of safety, and low cost. Salsalate has recently been shown to have glucose lowering effects. We propose to develop a clinical trial to evaluate the effect of Salsalate on DN. Our specific aims are: Aim 1: Develop a proposal for a multi-center randomized clinical trial to evaluate the effects of salsalate on measures of DN in patients with T1DM Aim 2: Develop the supporting materials needed to conduct the trial in Aim 1, develop the criteria of site selection, reach out to the sites of interest and finalize the selection process, and develop the general and site specific recruitment strategies. The accomplishment of these aims will allow implementing the proposed clinical trial protocol on a sample of subjects to test documents and procedures during the planning grant phase R34 and allow submission of an application for a multi-center trial grant. PUBLIC HEALTH RELEVANCE: This study is relevant to public health because diabetic neuropathy (DN) is the most common chronic complication of diabetes, ultimately affecting half of patients with diabetes and leading to severe morbidity, high mortality, major physical disability, and poor quality of life. This is relevant to the NIH mission because to date there is still no specific treatment for DN. We propose to use a FDA-approved drug commonly used to treat osteoarthritis, which has recently been shown to have glucose lowering effects, to address inflammation - a critical mediator in the development and progression of peripheral nerve damage in diabetes, and pain- the most common and cumbersome symptom for patients with DN.